1-aryloxy-3-(substituted alkylamino)-2-propanols and use as β-blocker

ABSTRACT

1-Aryloxy-3-(substituted alkylamino)-2-propanols having the general information: ##STR1## and their pharmaceutically acceptable salts exhibit cardioselective β-adrenergic blocking activity, and are useful as antihypertensive, cardioprotective, antiarrhythmic and, antianginal agents.

This is a division of application Ser. No. 054,094, filed May 18, 1987,now U.S. Pat. No. 4,766,541.

SUMMARY OF THE INVENTION

This invention is concerned with compounds of general structural formulaI: ##STR2## and pharmaceutically acceptable salts thereof wherein R¹,R², R³, n and Y are as defined below.

These novel compounds and their pharmaceutically acceptable saltsexhibit cardioselective β-adrenergic blocking activity, and are usefulas antihypertensive, cardioprotective, antiarrhythmic, and antianginalagents; and are useful in the treatment of elevated intraocularpressure.

BACKGROUND OF THE INVENTION

A class of pharmaceutical agents known as β-adrenergic blocking agents,are available which affect cardiac, vascular and pulmonary functions andare mild antihypertensives. β-adrenergic blocking agents, their chemicalstructure and activity, are disclosed in Clinical Pharmacology andTherapeutics, 10, 292-306 (1969). Various β-adrenergic blocking agentsare also described in the following patents: U.S. Pat. No. 3,048,387;U.S. Pat. No. 3,337,628; U.S. Pat. No. 3,655,663; U.S. Pat. No.3,794,650; U.S. Pat. No. 3,832,470; U.S. Pat. No. 3,836,666; U.S. Pat.No. 3,850,945; U.S. Pat. No. 3,850,946; U.S. Pat. No. 3,850,947; U.S.Pat. No. 3,852,291; U.S. Pat. No. 4,134,983; U.S. Pat. No. 4,199,580;U.S. Pat. No. 4,115,575; U.S. Pat. No. 4,195,090; British Pat. No.1,194,548; and South African Pat. No. 74/1070.

Now, with the present invention there are provided novel cardioselectiveβ-blocking agents which have the capability of reducing heart rate,without counteracting vasodepression or suppressing bronchodilation;processes for their synthesis, pharmaceutical formulations comprisingone or more of the novel compounds; and methods of treatment with thenovel compounds or pharmaceutical compositions thereof wherein anantihypertensive, cardioprotective, antiarrhythmic or antianginal agentis indicated.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of this invention are represented by the formula I:##STR3## or a pharmaceutically acceptable salt thereof, wherein: Y is

(1) a 6-membered heterocycle with 1 or 2 heteroatoms selected from O, Nand S such as morpholino, piperazino, N-C₁₋₃ alkylpiperazino, 2-, 3- or4-pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, or

(2) di(C₁₋₃ alkyl)amino;

R¹ is

(1) hydrogen,

(2) hydroxy, or

(3) hydroxymethyl;

R² and R³ are independently:

(1) hydrogen,

(2) halo such as chloro, bromo or fluoro,

(3) hydroxy,

(4) amino,

(5) di(C₁₋₅ alkyl)amino,

(6) mono(C₁₋₅ alkyl)amino,

(7) nitro,

(8) cyano,

(9) C₁₋₆ alkyl,

(10) C₃₋₈ cycloalkyl,

(11) C₂₋₅ alkenyl,

(12) C₁₋₄ alkoxy,

(13) C₁₋₄ alkylthio,

(14) C₂₋₅ alkenyloxy,

(15) C₁₋₅ alkanoyl, such as formyl, pentanoyl or the like.

n=2, 3 or 4

In a preferred embodiment of the compound of this invention R¹ and R²are hydrogen, R³ is cyano, and Y is morpholino, piperazino, N-(C₁₋₃alkyl)piperazino, pyrimidyl, pyrazinyl, 2-, 3-, or 4-pyridyl,pyridazinyl or dimethylamino; and n is 2.

The novel compounds of this invention include all the optical isomerforms as pure enantiomers or as mixtures containing the optical isomerssuch as racemic mixtures and compounds.

The compounds of the present invention also include the non-toxicpharmaceutically acceptable acid addition and quaternary ammonium salts.The acid addition salts are prepared by treating the compounds with anappropriate amount of a suitable organic or inorganic acid. Examples ofuseful organic acids are carboxylic acids such as maleic acid, tartaricacid, acetic acid, pamoic acid, oxalic acid, propionic acid, salicylicacid, succinic acid, citric acid, malic acid, isethionic acid, and thelike. Useful inorganic acids are hydrohalo acids such as hydrochloric,hydrobromic, hydriodic, sulfuric, phosphoric acid, or the like.

Compounds of the present invention may be prepared by any convenientmethod, however, the preferred methods utilized will depend upon the R¹,R², R³, R⁴ and Y groups. In the methods described below, the R¹ -R⁴ andY groups are as defined above unless otherwise indicated. Also, unlessotherwise indicated, the starting materials employed are known in theliterature, are commercially available, or can be prepared by methodsknown to those skilled in the art. ##STR4##

For Method A, an epoxide I is reacted with an appropriate amine, II in asuitable solvent such as methanol, ethanol, isopropanol, methylenechloride, THF or the like, at 0° C. to the reflux temperature of thesolvent for about 1-48 hours, preferably in isopropanol at 45° C. for 18hours, to yield III.

The novel compounds of this invention are active as cardioselectiveβ-adrenergic receptor blocking agents and hence useful asantihypertensive, cardioprotective, antiarrhythmic, and antianginalagents, and useful in the treatment of elevated intraocular pressure.

For use as antihypertensives and/or β-adrenergic blocking agents, thepresent compounds can be administered transdermally, orally orparenterally; i.e., intravenously, interperitoneally, etc. and in anysuitable dosage form. The compounds may be offered in a form (a) fororal administration; e.g., as tablets, in combination with othercompounding ingredients customarily used such as talc, vegetable oils,polyols, benzyl alcohols, gums, gelatin, starches and other carriers;dissolved or dispersed or emulsified in a suitable liquid carrier; incapsules or encapsulated in a suitable encapsulating material; or (b)for parenteral administration; e.g., dissolved or dispersed in asuitable liquid carrier or emulsifier; or (c) as an aerosol ordrug-impregnated patch for transdermal administration. Generally, dosesof the novel compounds of from about 0.01 to about 50 mg/kg/day andpreferably from about 0.1 to about 20 mg/kg of body weight per day areused. Dosage may be single or multiple depending on the daily totalrequired and the unit dosage.

The in vitro β-adrenergic blocking properties of the novel compounds ofthis invention were evaluated in accordance with standard procedures.The interaction with the β₁ -receptor was determined via inhibition ofthe positive chronotropic actions of isoproterenol in isolated guineapig atrial preparations. β₂ potency was determined by using isolatedguinea pig tracheal chains contracted with PGF₂α and by measuringinhibition of isoproterenol-induced relaxation.

Typical results are shown in the following table.

    ______________________________________                                         ##STR5##                                                                             pA.sub.2 values                                                                              Cardioselectivity                                      Y         β.sub.1 (atria)                                                                    β.sub.2 (trachea)                                                                   ratio                                          ______________________________________                                         ##STR6## 7.63      6.86       5.9                                             ##STR7## 7.46      4.46       1000                                            ##STR8## 7.13      6.52       4.1                                             ##STR9## 7.59      7.19       2.5                                             ##STR10##                                                                              7.81      7.05       5.8                                            N(CH.sub.3).sub.2                                                                       7.36      5.95       81.3                                           ______________________________________                                    

EXAMPLE 1 1-(2-Cyanophenoxy)3-[2-(4-pyridyl)ethyl]amino-2-propanol StepA: Preparation of 3-(2-Cyanophenoxy)-1,2-epoxypropane

2-Cyanophenol (99.8 g, 0.84 mole) and epichlorohydrin (192 ml) in 2NNaOH (575 ml) were heated at 40° C. for 11/2 hours. The reaction mixturewas allowed to cool to room temperature and extracted with CHCl₃ (2×350ml). The CHCl₃ extracts were combined, washed with H₂ O (2×300 ml) anddried over Na₂ SO₄. The CHCl₃ was removed in vacuo and the residue wascrystallized twice from ether. The product was separated by filtrationand dried in vacuo to yield 79 g (54%) of the desired epoxide, m.p.65°-67°.

Step B: Preparation of1-(2-Cyanophenoxy)-3-[2-(4-pyridyl)ethyl]amino-2-propanol

The epoxide from Step A was dissolved in a mixture of 2-propanol (50 ml)and CH₂ ClA₂ (20 ml) and added dropwise to a stirred solution of4-(2-aminoethyl)pyridine (3.05 g, 25 mmole) in 2-propanol (4 ml) at 60°C. The reaction mixture was stirred at 60° C. for 6 hours then wasallowed to cool to room temperature. The solvent was removed in vacuoand the product purified by chromatography on silica gel 60 (230-400mesh). The column was eluted with 95--5--0.5 (CHCl₃ --CH₃ OH--NH₄ OHv/v/v) to yield the product (3.3 g, 40%); m.p. 172° C.

Following the procedure substantially as described in Example 1 butsubstituting for 4-(2-aminoethyl)pyridine used in Step B thereof acorresponding amount of the amines of structure, H₂ N--(CH₂)₂ --Ydescribed in Table II there are produced the 1-aryloxy-3-(substitutedalkylamino)-2-propanols also described in Table II in accordance withthe following reaction scheme: ##STR11##

                                      TABLE II                                    __________________________________________________________________________    R.sup.1                                                                              R.sup.2   R.sup.3                                                                             n Y                                                    __________________________________________________________________________    H      H         2-CN  2                                                                                          (m.p. 114-116° C. .2HCl)           H      H         2-CN  2                                                                                ##STR12## (m.p. 110-112° C. 2HCl.1/2H.sub                                        .2 O)                                     H      H         2-CN  2                                                                                ##STR13## (m.p. 173-5° C. 2HCl)              H      H         2-CN  2                                                                                ##STR14## (m.p. 249-51° C. 3HCl)             H      H         2-CN  2 N(CH.sub.3).sub.2                                                                        (m.p.                                                                         160-62° C.)                        H      h         2-F   3                                                                                ##STR15##                                           5-OH   H         H     3                                                                                ##STR16##                                           5-HOCH.sub.2                                                                         H         H     4                                                                                ##STR17##                                           H      4-OH      H     4                                                                                ##STR18##                                           H      H         2-NH.sub.2                                                                          3                                                                                ##STR19##                                           H      3-N(CH.sub.3).sub.2                                                                     H     4                                                                                ##STR20##                                           H      3-CH.sub.3                                                                              2-NHCH.sub.3                                                                        2 N(CH.sub.3).sub.2                                    H      4-NO.sub.2                                                                              2-C.sub.2 H.sub.5                                                                   3                                                                                ##STR21##                                           H      3-OCH.sub.3                                                                             2-CH.sub.3                                                                          3                                                                                ##STR22##                                           H      H         2-C.sub.2 H.sub.5                                                                   2                                                                                ##STR23##                                           H      3-n-C.sub.3 H.sub.7                                                                     H     2                                                                                ##STR24##                                           H      H         2-n-C.sub.6 H.sub.14                                                                2                                                                                ##STR25##                                           H      3-c-C.sub. 3 H.sub.5                                                                    2-CH.sub.3                                                                          2                                                                                ##STR26##                                           H      H         2-c-C.sub.6 H.sub.11                                                                2 N(CH.sub.3).sub.2                                    H      4-CH.sub.2CHCH.sub.2                                                                    H     2                                                                                ##STR27##                                           H      H         2-OCH.sub.3                                                                          ##STR28##                                             H      3-oCH(CH.sub.3).sub.2                                                                   H     3                                                                                ##STR29##                                           H      H         2-SC.sub.2 H.sub.5                                                                  3                                                                                ##STR30##                                           H      4-OCHCHCH.sub.3                                                                         H     2                                                                                ##STR31##                                           H      H                                                                                        ##STR32##                                                                          2                                                                                ##STR33##                                                   ##STR34##                                                                              H     2 N(CH.sub.3).sub.2                                    __________________________________________________________________________

    ______________________________________                                        INGREDIENT        AMOUNT (Mg.)                                                ______________________________________                                        TABLET FORMULATION I                                                          1-(2-cyanophenoxy)-3-[2-(4-                                                                     40.0                                                        pyridyl)ethyl]amino-2-                                                        propanol                                                                      calcium phosphate 120.0                                                       CAPSULE FORMULATION                                                           1-(2-cyanophenoxy)-3-(2-                                                                        250                                                         piperazinylethyl)-                                                            amino-2-propanol                                                              trihydrochloride                                                              lactose, U.S.P.   93                                                          talc              7                                                           INJECTABLE SOLUTION                                                            1-(2-cyanophenoxy)-3-[2-                                                                       5                                                           (dimethylamino)ethyl]-                                                        amino-2-propanol                                                              sodium chloride   9                                                           distilled water, q.s. 1.0 ml.                                                 LIQUID SUSPENSION                                                              1-(2-cyanophenoxy)-3-[2-                                                                       5.0                                                         (4-pyridyl)ethyl]amino-                                                       2-propanol                                                                    Veegum H.V.       3.0                                                         methyl paraben    1.0                                                         kaolin            10.0                                                        glycerin          250.0                                                       water, q.s.       1 liter                                                     ______________________________________                                    

We claim:
 1. A compound of structural formula ##STR35## or apharmaceutically acceptable salt thereof, wherein: Y is a di(C₁₋₃alkyl)aminoR¹ is hydrogen; R² is hydrogen; R³ is cyano; and n is 2, 3 or4.
 2. The compound of claim 1 or a pharmaceutically acceptable saltthereof wherein Y is dimethylamino and n is
 2. 3. A pharmaceuticalβ-blocking composition comprising a pharmaceutical carrier and aneffective β-blocking amount of a compound of structural formula:##STR36## or a pharmaceutically acceptable salt thereof, wherein: Y is adi(C₁₋₃ alkyl)aminoR¹ is hydrogen; R² is hydrogen; R³ is cyano; and n is2, 3 or
 4. 4. The composition of claim 3 wherein Y is dimethylamino andn is
 2. 5. A method of treatment with a β-blocker which comprises theadministration to a patient in need of such treatment of an effectiveβ-blocking amount of a compound of structural formula: ##STR37## or apharmaceutically acceptable salt thereof, wherein: Y is a di(C₁₋₃alkyl)aminoR¹ is hydrogen; R² is hydrogen; R³ is cyano; and n is 2, 3 or4.
 6. The method of treatment of claim 5 wherein Y is dimethylamino andn is 2.